The overall goal of this Program Project is to identify the mechanisms that alter normal growth control to bring about neoplastic transformation. Cell proliferation is normally regulated by coordinated mechanisms that stimulate or inhibit growth and modulate differentiation and development. The overall focus of this program is the investigation of the basic control mechanisms through which growth inhibitory proteins and inducers of differentiation modulate cell proliferation and development. Alterations in these controls may lead to cancer. The program is composed of 3 projects that involve the use of biochemical, cell and molecular technologies and transgenic mouse models. Project 2 will use transgenic mice to investigate the role of TGFBeta in the regulation of mammary development, and will test the hypothesis that loss of TGFBeta inhibition and over production of TGFalpha promote development of mammary carcinoma. The mechanism by which TGFbeta inhibits proliferation will also be studied. Project 3 will use molecular biological techniques to determine the function of the three c-Myc proteins in the regulation of growth and differentiation. The capacity of Myc proteins to enhance transcription will be examined, and transgenic mice used to determine effects of the Myc proteins on the induction and suppression of breast tumors. Project 4 will investigate the role of DVR-6 in the growth and differentiation of specific cells and tissues in the mouse embryo. Misexpression of DVR-6 in transgenic mice and generation of DVR-6 null mutants will be used as complementary approaches to elucidate the function of DVR-6 in development. Thy synthesis, secretion and post-transnational modification of DVR-6 by a variety of cells will also be studied. The 3 research projects will be supported by two cores. This program brings together six investigators in 3 projects that integrate the study of cell proliferation with differentiation and development. The proposed studies focus on cell and animal models to characterize the process that alter normal growth control and lead to cancer.